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Peri-articular histiocytic sarcoma (PAHS) occurs in dogs, including Bernese Mountain Dogs (BMD). An etiologic relationship with previous joint disease has not been documented.
Peri-articular histiocytic sarcoma in BMD will be more frequently encountered around previously diseased joints compared with normal joints.
920 European BMD.
A retrospective...
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... of the 8 appendicular SCS was diagnosed on cytology and so excluded for immunohistochemistry. Immunolabeling with CD18 was positive on all 7 primary synovial tumors initially diagnosed as SCS on H&E staining and 4 randomly chosen PAHS, whereas none of them reacted with the pancytokeratin marker (Fig 1). Based on these findings, the tumors initially diagnosed as SCS were considered as PAHS for the study, including the SCS diagnosed on cytology. ...
Citations
... Histiocytic sarcoma (HS) is one of the most aggressive and fatal tumors originating from antigen-presenting myeloid dendritic cells (6,8,21). It can occur in the localized form, affecting mainly the skin and subcutaneous tissue, periarticular tissue, lungs, and spleen (32), or in the disseminated form (6,12,19). Despite the lack of knowledge about the etiopathogenesis of HS, the identification of genetics copy number aberrations (CNA) is frequent in Bernese Mountain Dog (BMD) and Flat-Coated Retriever (FCR), among them the loss of important chromosomal regions that can lead to the malignant transformation of histiocytes (11,29,32). ...
... It can occur in the localized form, affecting mainly the skin and subcutaneous tissue, periarticular tissue, lungs, and spleen (32), or in the disseminated form (6,12,19). Despite the lack of knowledge about the etiopathogenesis of HS, the identification of genetics copy number aberrations (CNA) is frequent in Bernese Mountain Dog (BMD) and Flat-Coated Retriever (FCR), among them the loss of important chromosomal regions that can lead to the malignant transformation of histiocytes (11,29,32). This neoplasm affects dogs from 2 to 13 years old (2,18) and has a higher occurrence in BMD (14) and FCR (10), but there are reports in several breeds (6,17). ...
Histiocytic sarcoma is a neoplasm originating from the dendritic cell lineage and presents an aggressive biological behavior and poor prognosis due to its increased metastatic rate. It can be localized, such as the articular and periarticular forms, or disseminated to several organs. Histopathological examination associated with immunohistochemistry can lead to a definitive diagnosis. The treatment of choice is surgical excision, chemotherapy, radiotherapy, or combination. Here, we report a case of periarticular histiocytic sarcoma involving the left knee joint in a female French Bulldog. The animal showed signs of lameness, a mass in the left pelvic limb, and radiographic findings suggestive of neoplasia. After cytological examination suggesting malignant mesenchymal neoplasia, the limb was amputated, and histiocytic sarcoma was diagnosed by histopathological examination and positive immunohistochemistry for CD18 and IBA1. After amputation, multimodal chemotherapy was instituted, and the animal survived for nine months from the start of chemotherapy treatment. However, the patient presented metastasis to the lungs, right pelvic limb, and superficial inguinal and popliteal lymph nodes.
... Interestingly the vast majority (78.1%) of LHS leading to lameness was located in the front legs in the FCR, while in the BMD, there was a more even distribution. An association with prior joint disease was reported before for several breeds [38,39]; however, this association was absent in FCR. ...
Histiocytic sarcoma (HS) is an aggressive malignant tumor of histiocytes, which can affect almost any organ in the body and is characterized by a broad array of tumor locations and clinical presentations. So far, no complete overview exists of the array of clinical aspects of HS in specific dog breeds in large groups. Therefore, we investigated the clinical characteristics of HS in a population of Bernese Mountain Dogs (BMD; n = 365) and Flat-Coated Retrievers (FCR; n = 289), which are two of the most affected dog breeds. Cases were selected from databases from different pathology services, and clinical information was retrospectively collected for each case. Localized HS was reported significantly more frequently in the FCR (60.6%) than in the BMD (39.2%), and disseminated HS was recorded significantly more frequently in the BMD (60.8%) than in the FCR (39.4%). Lameness was seen more often in FCR than in BMD, and the vast majority (78.1%) of LHS leading to lameness was located in the front legs in the FCR, while in the BMD, there was a more even distribution. BMD had significantly more often leukocytosis and thrombocytopenia, even corrected for the type of HS, than FCR. No significant difference in the frequency of anemia was recorded between BMD and FCR. In those dogs in which blood examination was performed, hypercalcemia was diagnosed in 15 BMD, while none of the FCR had hypercalcemia. The new information provided in this study can aid the diagnostic process and allow for prompt treatment recommendations.
... bmdca.org/health/diseases.php) [48,49]. While no causal relationship was found between inflammation and HS, inflammation is suspected to contribute to HS development [50][51][52]. Thus, it is not surprising that HS GWAS hits overlap not only candidate tumor suppressor genes (TUSC1; tumor suppressor candidate 1) or other well-known tumor suppressors involved in cell cycle (CDKN2A), genome stability (telomere protection: POT1, replication stress/DNA damage: FHIT) but also inflammation (IL17rd, SPNS3, ARHGEF3; S5 Table). ...
Histiocytic sarcoma (HS) is a rare but aggressive cancer in both humans and dogs. The spontaneous canine model, which has clinical, epidemiological, and histological similarities with human HS and specific breed predispositions, provides a unique opportunity to unravel the genetic basis of this cancer. In this study, we aimed to identify germline risk factors associated with the development of HS in canine-predisposed breeds. We used a methodology that combined several genome-wide association studies in a multi-breed and multi-cancer approach as well as targeted next-generation sequencing, and imputation We combined several dog breeds (Bernese mountain dogs, Rottweilers, flat-coated retrievers, and golden retrievers), and three hematopoietic cancers (HS, lymphoma, and mast cell tumor). Results showed that we not only refined the previously identified HS risk CDKN2A locus, but also identified new loci on canine chromosomes 2, 5, 14, and 20. Capture and targeted sequencing of specific loci suggested the existence of regulatory variants in non-coding regions and methylation mechanisms linked to risk haplotypes, which lead to strong cancer predisposition in specific dog breeds. We also showed that these canine cancer predisposing loci appeared to be due to the additive effect of several risk haplotypes involved in other hematopoietic cancers such as lymphoma or mast cell tumors as well. This illustrates the pleiotropic nature of these canine cancer loci as observed in human oncology, thereby reinforcing the interest of predisposed dog breeds to study cancer initiation and progression.
... Indeed HS predisposed breeds, especially BMD, are also predisposed to reactive histiocytic diseases 41 but also to other immune or inflammatory diseases such as glomerulonephritis, aseptic meningitis or inflammatory bowel disease (https://www.bmdca.org/health/diseases.php) 42,43 . While no causal relationship was proved between inflammation and HS, inflammation is suspected to contribute to HS development [44][45][46] . In these conditions it is not surprising that HS GWAS hits overlap not only candidate tumor suppressor genes (TUSC1) or well-known tumor suppressors involved in cell cycle (CDKN2A), in genome stability (telomere protection: POT1, replication stress/DNA damage: FHIT…) but also in inflammation (IL17a, Table 7). ...
Histiocytic sarcoma (HS) is a rare but aggressive cancer in humans and dogs. The spontaneous canine model, with the clinical, epidemiological and histological similarities with human HS and specific breed predispositions, is a unique model/opportunity to unravel the genetic bases of this cancer. In this study, we aimed to identify germline risk factors associated with the development of HS in canine predisposed breeds. We used a methodology that combined several genome-wide association studies in a multi-breed and multi-cancer approach, as well as targeted next generation sequencing, and imputation combining several breeds (Bernese mountain dog, Rottweiler, flat coated retriever and golden retriever) and three haematopoietic cancers (HS, lymphoma and mast cell tumor). Results showed that we not only refined the previously identified HS risk CDKN2A locus but we identified new loci on canine chromosomes 2, 5, 12, 14, 20, 26 and X. Capture and targeted sequencing of specific loci pointed towards the existence of regulatory variants in non coding regions and/or methylation mechanisms linked to risk haplotypes, leading to strong cancer predispositions in specific dog breeds. Our results showed that these canine cancer predisposing loci appear to be due to the additive effect of several risk haplotype involved also in other haematopoietic cancers such lymphoma or mast cell tumor, illustrating the pleiotropic nature of these canine cancer loci as observed in human oncology.
... In the absence of a defined intracranial subdural space, both primary and disseminated HS involve both the meninges and the brain parenchyma, and most other intracranial neoplasia is not associated with marked CSF pleocytosis, [22][23][24] also supporting an argument for inherent differences in the pro-inflammatory nature of the primary versus disseminated HS subtypes. Articular or periarticular HS also has been associated with a marked inflammatory response, 8 and associations have been made between prior injury and inflammation involving the joint and the development of HS. 38,39 No direct evidence supports underlying inflammation as a predisposing factor for the development of HS, but the link between inflammation and a variety of cancers is well documented. 40 Further investigation is warranted to determine whether preexisting inflammation may be a precursor for primary CNS HS and whether specific breeds may have genetic predispositions consistent with this pathogenic mechanism. ...
Background
Histiocytic sarcoma affecting the central nervous system (CNS HS) in dogs may present as primary or disseminated disease, often characterized by inflammation. Prognosis is poor, and imaging differentiation from other CNS tumors can be problematic.
Objective
To characterize the clinicopathological inflammatory features, breed predisposition, and survival in dogs with CNS HS.
Animals
One hundred two dogs with HS, 62 dogs with meningioma.
Methods
Retrospective case series. Records were reviewed for results of cerebrospinal fluid (CSF) analysis, CBC, treatment, and outcome data.
Results
Predisposition for CNS HS was seen in Bernese Mountain Dogs, Golden Retrievers, Rottweilers, Corgis, and Shetland Sheepdogs (P ≤ .001). Corgis and Shetland Sheepdogs had predominantly primary tumors; Rottweilers had exclusively disseminated tumors. Marked CSF inflammation was characteristic of primary rather than disseminated HS, and neoplastic cells were detected in CSF of 52% of affected dogs. Increased neutrophil to lymphocyte ratios were seen in all groups relative to controls (P <.008) but not among tumor subtypes. Definitive versus palliative treatment resulted in improved survival times (P < .001), but overall prognosis was poor.
Conclusions and Clinical Importance
Clinicopathological differences between primary and disseminated HS suggest that tumor biological behavior and origin may be different. Corgis and Shetland Sheepdogs are predisposed to primary CNS HS, characterized by inflammatory CSF. High total nucleated cell count and the presence of neoplastic cells support the use of CSF analysis as a valuable diagnostic test. Prognosis for CNS HS is poor, but further evaluation of inflammatory mechanisms may provide novel therapeutic opportunities.
... In humans, CD68, lysozyme, and CD163 are markers designated for use for HS, with the latter considered of highest specificity (9,38,39). The diagnosis in dogs is based on different cell markers, CD18 (25,28,29,40), a leukocyte integrin, and CD204, a macrophage scavenger receptor (41,42). Thongtharb and colleagues reported a strong positive expression of CD163 in 17 of 23 cases of canine HS, suggesting that CD163 might be a common marker between the two species (43). ...
... A comprehensive characterization of the BD cell line was recently published by our group (44).To confirm the histiocytic phenotype, we used two markers that are routinely used to diagnose canine HS: CD18 (integrin beta chain beta 2) and CD204 (class A macrophage scavenger receptor; refs. 25,28,29,40,42). All three cell lines were positive for both markers by IHC, while negative for CD3 and CD79a, ruling out a lymphoid phenotype ( Supplementary Fig. S1). ...
Histiocytic sarcoma in humans is an aggressive orphan disease with a poor prognosis as treatment options are limited. Dogs are the only species that spontaneously develops histiocytic sarcoma with an appreciable frequency, and may have value as a translational model system. In the current study, high throughput drug screening utilizing histiocytic sarcoma cells isolated from canine neoplasms identified these cells as particularly sensitive to a MEK inhibitor, trametinib. One of the canine cell lines carries a mutation in PTPN11 (E76K), and another one in KRAS (Q61H), which are associated with the activation of oncogenic MAPK signaling. Both mutations were previously reported in human histiocytic sarcoma. Trametinib inhibited sensitive cell lines by promoting cell apoptosis, indicated by a significant increase in caspase 3/7. Furthermore, in vitro findings were successfully re-capitulated in an intrasplenic orthotopic xenograft mouse model which represents a disseminated aggressive form of histiocytic sarcoma. Mice with histiocytic sarcoma xenograft neoplasms that were treated with trametinib had significantly longer survival times. Target engagement was validated as activity of ERK, downstream of MEK, was significantly downregulated in neoplasms of treated mice. Additionally, trametinib was found in plasma and neoplastic tissues within projected therapeutic levels. These findings demonstrate that in dogs, histiocytic sarcoma may be associated with a dysfunctional MAPK pathway, at least in some cases, and may be effectively targeted through MEK inhibition. Clinical trials to test safety and efficacy of trametinib in dogs with histiocytic sarcoma are warranted, and may provide valuable translational information to similar diseases in humans.
... Fresh post-mortem tissue samples from both an abdominal and a pulmonary neoplasm were aseptically obtained from an 8-year-old spayed female BMD presented to the Michigan State University Veterinary Teaching Hospital. The diagnosis of HS was based on histopathology findings of the tumor and positive staining for CD18 by immunohistochemistry ( Fig. 1) [8,15,30,31]. ...
... Histiocytic sarcomas are frequently associated with a high level of cellular pleomorphism, therefore, the definitive diagnosis is determined by a pattern of expression of markers specific for histiocytes. Although, several markers have been used to characterize human HS including CD163, CD68, CD11c, lysozyme, and CD14 [4,32,33], two different markers were validated for HS tumors in dogs: CD18 (integrin beta chain beta 2) and CD204 (class A macrophage scavenger receptor) [8,15,30,31,34]. The novel BD cell line showed positive expression of CD18 and CD204, consistent with the diagnosis of HS. ...
Background:
Histiocytic sarcoma is a rare disorder in humans, however it is seen with appreciable frequency in certain breeds of dogs, such as Bernese mountain dog. The purpose of this study was to fully characterize a novel canine histiocytic sarcoma cell line, and utilize it as a tool to screen for potential therapeutic drugs.
Methods:
The histiocytic sarcoma cell line was characterized by expression of cellular markers as determined by immunohistochemistry and flow cytometry techniques. The neoplastic cells were also evaluated for their capability of phagocytizing beads particles, and their potential to grow as xenograft in an immunodeficient mouse. We investigated the in vitro cytotoxic activity of a panel of thirteen compounds using the MTS proliferation assay. Inhibitory effects of different drugs were compared using one-way ANOVA, and multiple means were compared using Tukey's test.
Results:
Neoplastic cells expressed CD11c, CD14, CD18, CD45, CD172a, CD204, MHC I, and vimentin. Expression of MHC II was upregulated after exposure to LPS. Furthermore, the established cell line clearly demonstrated phagocytic activity similar to positive controls of macrophage cell line. The xenograft mouse developed a palpable subcutaneous soft tissue mass after 29 days of inoculation, which histologically resembled the primary neoplasm. Dasatinib, a tyrosine kinase pan-inhibitor, significantly inhibited the growth of the cells in vitro within a clinically achievable and tolerable plasma concentration. The inhibitory response to dasatinib was augmented when combined with doxorubicin.
Conclusions:
In the present study we demonstrated that a novel canine histiocytic sarcoma cell line presents a valuable tool to evaluate novel treatment approaches. The neoplastic cell line favorably responded to dasatinib, which represents a promising anticancer strategy for the treatment of this malignancy in dogs and similar disorders in humans.
... Other investigated potential risk factors for HS in dogs include environmental exposures, previous medical history and prior orthopaedic disease. 14,15 In a retrospective study of Bernese Mountain Dogs, orthopaedic disease was determined to be a predisposing factor associated with the development of HS. Dogs with prior orthopaedic disease were 2.5 times more likely to develop HS than those without. ...
... Interestingly, dogs in the same study treated with prescription anti-inflammatory medications were at a lower risk for development of HS. 14 In another study, Bernese Mountain Dogs were found to be 5.4 times more likely to develop PAHS in a previously diseased joint compared with a healthy joint. 15 An association in Rottweilers between prior joint disease and PAHS was suggested by Craig et al; 62% of Rottweilers with PAHS of the stifle were found to have previous cranial cruciate ligament rupture in the tumouraffected joint. 8 There are also individual reports in dogs of other breeds (Flat Coated Retriever and Golden Retriever) developing PAHS in a previously diseased joint. ...
... In our study, we did not find a significant association between prior joint disease and PAHS affecting the elbow, in contrast to previous studies in Bernese Mountain Dogs. 15 It is possible that the lack of significant association in the elbow group was exaggerated by difficulty in diagnosing elbow disease. Four dogs in this study were diagnosed with cruciate rupture based on physical examination alone. ...
Periarticular histiocytic sarcoma (PAHS) is the most common synovial tumour in dogs and is characterized by aggressive local disease with a high rate of distant metastasis. Previously, an association between PAHS and prior joint disease has been demonstrated in the Bernese Mountain Dog breed and suggested in the Rottweiler. We hypothesized that this association would be present in other breeds and investigated this via a retrospective, case-controlled analysis. Cases were dogs diagnosed with PAHS of the stifle or elbow. Controls were age, breed and sex-matched dogs without a diagnosis of histiocytic sarcoma. Diagnosis of prior joint disease was determined based on review of medical records and direct veterinarian and owner communications. Data were evaluated using logistic regression, 2-sampled t tests, and chi-squared analysis. Our study population consisted of 28 cases and 46 controls, including Flat-Coated, Golden and Labrador Retrievers, Rottweilers, English Bulldogs, Shih Tzus, Australian Shepherds, Staffordshire Terriers and mixed breed dogs. Dogs with PAHS were more likely to have prior joint disease in the tumour-affected joint compared with the control population (odds ratio [OR] = 13.42, P < .0001, 95% confidence interval [CI] = 4.33-48.63). A total of 88.2% of dogs with stifle PAHS had prior joint disease in their tumour-affected joint, most commonly cranial cruciate ligament rupture. This study confirms that the previously noted association between prior joint disease and PAHS in Bernese Mountain Dogs also applies to other breeds. Additional studies are needed to further investigate for a causal relationship.
... Inflammation of the adjacent synovium with lymphocyte, plasma cells, and histiocytes is also observed. 18 A history of anterior cruciate rupture or other traumatic injury to joints is associated with the development of articular HS. 18,82 Synovitis has been reported in association with rupture of the cranial cruciate ligament. T cells and dendritic cells are major components of the inflammatory response. ...
Histiocytic proliferative disorders are commonly observed in dogs and less often cats. Histiocytic disorders occur in most of the dendritic cell (DC) lineages. Canine cutaneous histiocytoma originates from Langerhans cells (LCs) indicated by expression of CD1a, CD11c/CD18, and E-cadherin. When histiocytomas occur as multiple lesions in skin with optional metastasis to lymph nodes and internal organs, the disease resembles cutaneous Langerhans cell histiocytosis of humans. Langerhans cell disorders do not occur in feline skin. Feline pulmonary LCH has been recognized as a cause of respiratory failure due to diffuse pulmonary infiltration by histiocytes, which express CD18 and E-cadherin and contain Birbeck's granules. In dogs and cats, histiocytic sarcomas (HS) arise from interstitial DCs that occur in most tissues of the body. Histiocytic sarcomas begin as localized lesions, which rapidly disseminate to many organs. Primary sites include spleen, lung, skin, brain (meninges), lymph node, bone marrow, and synovial tissues of limbs. An indolent form of localized HS, progressive histiocytosis, originates in the skin of cats. Hemophagocytic HS originates in splenic red pulp and bone marrow macrophages in dogs and cats. In dogs, histiocytes in hemophagocytic HS express CD11d/CD18, which is a leuko-integrin highly expressed by macrophages in splenic red pulp and bone marrow. Canine reactive histiocytic diseases, systemic histiocytosis (SH) and cutaneous histiocytosis, are complex inflammatory diseases with underlying immune dysregulation. The lesions are dominated by activated interstitial DCs and lymphocytes, which invade vessel walls and extend as vasocentric infiltrates in skin, lymph nodes, and internal organs (SH).
Histiocytic sarcoma (HS) is a rare neoplasm of macrophages or dendritic cells with a poor prognosis in dogs. As the apoptosis inhibitor of macrophage (AIM) is characteristically expressed in canine macrophages, we hypothesised that AIM is involved in the development or progression of HS in dogs. In this study, AIM expression in the tumour region and serum AIM levels in dogs with HS was assessed. Additionally, the effects of AIM overexpression on HS cell viability were investigated using a HS cell line that was selected from five validated HS cell lines. Immunohistochemistry showed that AIM expression was observed in the cytoplasm of the HS cells. CD36, a candidate AIM receptor, was also observed on the cell membrane of HS cells. When the serum AIM level was detected in 36 dogs with HS and 10 healthy dogs via western blot analysis, the AIM levels in the HS dogs were significantly higher than those in the controls. AIM mRNA expression in the 5 HS cell lines varied but was higher than that in the other tumour-derived lines. Among the five HS cell lines, DH82 originally had lower AIM and the highest CD36 expression. When AIM was overexpressed in DH82, therein cell growth speed and invasion, apoptosis inhibition and phagocytic activity were strongly upregulated. These data suggest that elevated intra-tumour expression of AIM could induce the progression of HS cells in dogs. Moreover, elevated serum AIM levels in dogs with HS could serve as a biomarker of HS.
